1. Field of the Invention
The present invention relates to processes for preparing optically active .alpha.-arylalkanoic acids and the novel intermediates utilized therein. In particular, it relates to a stereoselective process for the preparation of optically active .alpha.-arylalkanoic acids by the oxidative coupling of the .alpha.-substituted metal or metal salt of an acid or derivative of an acid with an aryl halide in the presence of a chiral (optically active) transition metal catalyst, optionally in the presence of a dipolar, aprotic solvent. Optionally, concomitant or sequential hydrolysis of the derivative, such as the ester, amide, oxazoline, nitrile or carboxylic metal salt formed produces the corresponding optically active .alpha.-arylalkanoic acid. The process optionally includes the subsequent removal of halogen from the aromatic portion of the .alpha.-arylalkanoic acid. The process further includes subsequent formation of the pharmaceutically acceptable salts and esters of the optically active .alpha.-arylalkanoic acids. The products are pharmaceutical agents which have anti-inflammatory, analgesic and anti-pyretic activities.
2. State of the Art
Numerous .alpha.-arylalkanoic acids (i.e. 2-arylalkanoic acids) have been described and developed and found to be useful as pharmaceutical agents exhibiting anti-inflammatory, analgesic and anti-pyretic activity. For example, U.S. Pat. No. 3,385,386, describes certain 2-phenylpropionic acids useful for their anti-inflammatory activity. Particularly noteworthy of the compounds described therein is 2-(4-isobutylphenyl)propionic acid, known generically as ibuprofen. U.S. Pat. No. 3,600,437 describes 2-(3-phenoxyphenyl)- and 2-(3-phenylthiophenyl)alkanoic acids among other related compounds. Particularly noteworthy therein is the compound 2-(3-phenoxyphenyl)propionic acid, which is known generically as fenoprofen. U.S. Pat. No. 3,624,142 describes (fluoro-substituted biphenyl)alkanoic acids, among which is 2-(4'-fluoro-4-biphenyl)propionic acid. U.S. Pat. No. 3,755,427 describes additional fluoro-substituted biphenylpropionic acids, among which is 2-(2-fluoro-4-biphenyl)propionic acid, known as flurbiprofen. U.S. Pat. No. 3,904,682 describes the compound 2-(6-methoxy-2-naphthyl)propionic acid, which is known generically as naproxen and is a potent anti-inflammatory compound. Related compounds are described in Belgian Pat. No. 747,812. U.S. Pat. No. 3,912,748 describes 5- and 6-benzoxyazoyl-alkanoic acids possessing anti-inflammatory, anti-pyretic and analgesic activity. Notable among those compounds is 2-(4-chlorophenyl-5-benzoxazoyl)-propionic acid, known generically as benoxaprofen. Thus, it can be seen that a tremendous variety of useful .alpha.-arylalkanoic acids are known.
Other known, useful .alpha.-arylalkanoic acids are exemplified by 6-chloro-.alpha.-methyl-9H-carbazole-2-acetic acid (carprofen), .alpha.-methyl-9H-fluorene-2-acetic acid (cicloprofen), 3-chloro-.alpha.-methyl-4-(2-thienylcarbonyl)benzene acetic acid (cliprofen), .alpha.-methyl-3-phenyl-7-benzofuranacetic acid (furaprofen), 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzene acetic acid (indoprofen), 3-benzoyl-.alpha.-methylbenzene acetic acid (ketoprofen), 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)benzeneacetic acid (pirprofen), .alpha.-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) and compounds related thereto.
Numerous processes for the manufacture of such .alpha.-arylalkanoic acids have also been described. Such processes have been described in the aforementioned patents, and in other patents and in the non-patent literature as well. For example, U.S. Pat. No. 4,135,051 describes a process for preparing the ester precursors of many arylalkanoic acids utilizing trivalent thallium salts as reactants. Such a process suffers from the disadvantage that the thallium salts employed are toxic chemicals which must be removed from the final product. U.S. Pat. No. 3,975,431 describes the preparation of .alpha.-arylalkanoic acids from glycidonitriles through enol acylates. U.S. Pat. Nos. 3,658,863; 3,663,584; 3,658,858; 3,694,476; and 3,959,364 describe various coupling methods for preparing arylalkanoic acids. More recently, U.K. Patent publication No. 2,042,543, published Sept. 24, 1980, (corresponding to application Ser. No. 8005752, filed Feb. 20, 1980) describes a process for preparing the ester precursor of arylalkanoic acids from .alpha.-haloalkyl aryl ketones using a metal catalyst for catalytically inducing rearrangement in an acidic, alcoholic medium, the catalyst being silver (I) salts of organic and/or inorganic anions. The high costs associated with utilizing certain metal catalysts, particularly silver catalysts, in a large scale process is an inherent disadvantage to such a process.
U.S. Pat. No. 3,652,683 describes the preparation of 2-(6-methoxy-2-naphthyl)propionic acid by reacting a 2-(1-haloethyl)-6-methoxynaphthylene with nickel carbonyl in a lower tertiary alkanol solvent in the presence of an alkyl metal tertiary alkoxide until the ester is formed, and subsequently hydrolyzing the ester group thereof.
U.S. Pat. No. 3,651,106 describes a coupling of ethyl naphthalene derivatives, substituted in the .alpha.-position with a metal with: (a) carbon dioxide to produce the corresponding carboxylic acid; (b) ethyl orthocarbonate to produce the corresponding ester; (c) ethyl chloroformate; or (d) paraformaldehyde to produce the corresponding aldehyde which is reacted further to produce the corresponding 2-(6-methoxy-2-naphthyl)propionic acid.
Additional related patents include U.S. Pat. Nos. 3,076,016; 3,907,850; 4,017,526; 4,055,582; 4,120,882; 4,133,963; 4,142,054; 4,144,259; 4,293,502; 4,239,914; and 4,306,086, all of which are incorporated herein by reference.
The production of .alpha.-arylalkanoic acids by the arylation of BrZn--CH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3 using unsubstituted aromatic halides has been reported by J. F. Fauvarque and A. Jutand in the Journal of Organometallic Chemistry, Vol. 177, pp. 273-281 (1979).
The preparation of phenyl alkylcarboxylic acid esters by treatment of the corresponding .alpha.-lithium substituted carboxylic ester with unsubstituted phenyl halides in the presence of an inorganic nickel halide catalyst and a dipolar aprotic solvent, was reported by A. A. Millard and M. W. Rathke in J. Amer. Chem. Soc., Vol. 99, pp. 4833-4837 (1977). Other reactions of Grignard reagents with alkyl halides in the presence of a catalyst have been reported by T. Hayashi, et al., J. Amer. Chem. Soc., Vol. 104, pp. 180-186 (1982); T. Hayashi, et al., J. Amer. Chem. Soc., Vol. 98, pp. 371-819, (1976); K. Tamao, et al., Bulletin of the Chemical Society of Japan, Vol. 49, No. 7, pp. 1958-1969 (1976); and T. Hayashi, et al., Tet. Lett., Vol. 21, pp. 79-82 (1980).
B. J. Wakefield, in the Chemistry of Organolithium Compounds, published by Pergamon Press of New York in 1974, and references cited therein discusses the reverse metal-halogen exchange for organolithium compounds. This reaction appears to require highly activated unsaturated or alkyl-multiple halogen compounds to occur with organolithium compounds, and because optically active acids are obtained from the process, the exchange is not expected in the process of this invention. Similarly, T. Baer and R. Carney in Tetrahedron Letters, No. 51, pp. 4697-4700 published in 1976 discuss the copper catalyzed reaction of Grignard reagents with chloromagnesium salts of lower case .omega.-bromoacids.
Notwithstanding the usefulness of the aforesaid processes in many respects, there still remains a need for a simple process for producing optically active .alpha.-arylalkanoic acids of the types described. A number of the .alpha.-arylalkanoic acids exist as a mixture of optical isomers. It is often advantageous to have a stereoselective process for producing the desired optically active isomer of the .alpha.-arylalkanoic acid which displays all or a major portion of the pharmaceutical activity. For example, the isomer d 2-(6-methoxy-2-naphthyl)propionic acid is more pharmaceutically active than the 1-isomer. Therefore, it is desirable to have a stereoselective process for producing the d-isomer directly. Such a process obviates the necessity of subsequently resolving the d- and 1-isomers using optically active bases, such as cinchonidine, brucine, and the like. The elimination of the resolution steps results in a substantial savings, both in material cost and manufacturing labor and equipment. The savings can be particularly significant with regard to compounds which are approved for pharmaceutical use as a substantially pure, optically active isomer, such as d 2-(6-methoxy-2-naphthyl)propionic acid (naproxen) or a precursor which may be easily converted to this acid.